The major histocompatibility complex (MHC) antigens, HLA antigens in man, are of fundamental importance in generating, regulating, and effecting an immune response to foreign antigens. Products of the class II genes, as well as the associated invariant chain, are expressed primarily on the surfaces of B lymphocytes, macrophages, but now have been observed on many other types of cells. Although class II antigens are known to participate in antigen presentation and regulation in the immune response, and probably also as signals for differentiation, their functions are not completely understood. Regulation of class II genes must be finely tuned. Aberrant or imbalanced class II expression may trigger several autoimmune diseases and may help malignant cells evade an immune response. We propose experiments to identify regulatory genes required for class II expression using somatic cell genetics. In addition, we will investigate the nature of controls of transcription and processing of the class II products. Because different tissue types may use varying mechanisms to regulate class II genes, we will analyze class II expression in the B lymphoid cells and in several cell lines derived from metastatic melanomas which regulate class II expression in different ways. These systems were chosen because they should allow us to compare regulation in two distinct cell lineages and help us determine how controls are abrogated in disease states. At least three subgroups of homologous genes are encoded in the HLA class II region, and several of the genes for well characterized class Ii antigens, DP, DQ, and DR, have been cloned and analyzed. We will compare the mechanisms which control regulation at each sublocus. In addition, new genes, such as DZ, DO, and DX, have been found; and it is possible that there are other genes that are not yet identified within the class II region. Our analysis of the tissue distribution of each class II sublocus product, and examination of their differential regulation, will lead to a better understanding of the mechanisms of eukaryotic gene regulation.